Monica M França1, Mariana F A Funari1, Antonio M Lerario1,2,3, Mirian Y Nishi1,3, Carmem C Pita1, Eveline G P Fontenele4, Berenice B Mendonca5,6. 1. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 2. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA. 3. Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 4. Serviço de Endocrinologia e Diabetes do Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil. 5. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. beremen@usp.br. 6. Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. beremen@usp.br.
Abstract
PURPOSE: Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. METHODS: All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing. RESULTS: The novel homozygous c.1489delT variant in the NOBOX gene was identified in the two sisters with POF. Their parents were heterozygous carriers of this variant and, therefore, consistent with an autosomal recessive mode of inheritance. The c.1489delT NOBOX variant has not been previously reported in any public available databases (1000Genomes, 6500ESP/EVS, ExAC, and gnomAD). Furthermore, this variant was neither present in 387 Brazilian exomes control individuals nor in 200 fertile Brazilian women screened by Sanger sequencing. CONCLUSION: We report the first familial case of a novel homozygous NOBOX variant with an autosomal recessive mode of inheritance, thus allowing for a genetic diagnosis of primary ovarian failure.
PURPOSE:Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. METHODS: All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing. RESULTS: The novel homozygous c.1489delT variant in the NOBOX gene was identified in the two sisters with POF. Their parents were heterozygous carriers of this variant and, therefore, consistent with an autosomal recessive mode of inheritance. The c.1489delTNOBOX variant has not been previously reported in any public available databases (1000Genomes, 6500ESP/EVS, ExAC, and gnomAD). Furthermore, this variant was neither present in 387 Brazilian exomes control individuals nor in 200 fertile Brazilian women screened by Sanger sequencing. CONCLUSION: We report the first familial case of a novel homozygous NOBOX variant with an autosomal recessive mode of inheritance, thus allowing for a genetic diagnosis of primary ovarian failure.
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Authors: Monica M Franca; Xingfa Han; Mariana F A Funari; Antonio M Lerario; Mirian Y Nishi; Eveline G P Fontenele; Sorahia Domenice; Alexander A L Jorge; David Garcia-Galiano; Carol F Elias; Berenice B Mendonca Journal: J Clin Endocrinol Metab Date: 2019-07-01 Impact factor: 5.958
Authors: Monica M França; Mariana F A Funari; Antonio M Lerario; Mariza G Santos; Mirian Y Nishi; Sorahia Domenice; Daniela R Moraes; Everlayny F Costalonga; Gustavo A R Maciel; Andrea T Maciel-Guerra; Gil Guerra-Junior; Berenice B Mendonca Journal: PLoS One Date: 2020-10-23 Impact factor: 3.240